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Effect of denervation on mitochondrial function and the expression of apoptotic related proteins
Author(s) -
O’Leary Michael F.N.,
Adhihetty Peter J.,
Hood David A.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a388-a
Subject(s) - denervation , tunel assay , medicine , mitochondrion , apoptosis , endocrinology , muscle atrophy , skeletal muscle , reactive oxygen species , fragmentation (computing) , atrophy , biology , chemistry , microbiology and biotechnology , biochemistry , ecology
Chronic skeletal muscle disuse results in a loss of muscle mass which is partly attributable to apoptosis. This study was designed to evaluate the relationship between changes in mitochondrial function and apoptosis in chronic denervation (7, 14, 21 days) of rat tibialis anterior (TA) muscle. Denervation decreased state 3 (ADP‐stimulated) respiration in subsarcolemmal (SS) mitochondria by 37 – 45 % between 7 and 21 days, whereas no changes were evident in intermyofibrillar (IMF) mitochondria. Conversely, state 4 respiration increased by 68% in IMF mitochondria with 14 days of denervation, while it remained unchanged in the SS mitochondria. This was accompanied by a 2.3‐fold increase in UCP3 expression at 14 days of denervation. The expression of the anti‐oxidant enzyme MnSOD declined 60–70% in SS and IMF mitochondria, whereas the production of reactive oxygen species (ROS) was elevated 5–10‐fold in the SS mitochondrial subfraction. In addition, there was a 76% increase in the expression of the pro‐apoptotic protein p53 at 14 days of denervation. This was matched by an increase in DNA fragmentation, assessed using TUNEL staining. An elevation in apoptotic nuclei was evident as early as 7 days, which remained similarly elevated at 14 and 21 days. Thus chronic muscle denervation: 1) induces impairments in mitochondrial function, leading to increased ROS production; and 2) increases the expression of pro‐apoptotic proteins while reducing the protective effects of anti‐oxidant enzymes. These data suggest that mitochondrially mediated apoptosis contributes to the muscle atrophy which is observed during muscle disuse.